Hitman: Blood Money is the fourth game in the series, which was preceded by hit game Hitman: Contracts. It follows Agent 47 through a whole new line of assassination missions which take him all over the United States, from the life of a Mardi Gras parade and the lights of Las Vegas to the peace and quiet of the Mississippi river and a country home. It was released in mid-2006 and became the first game in the Hitman series to be on a next generation console (Xbox 360).

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One of the main improvements seen in Blood Money is the ability to hide bodies

There is a large variety of missions in Hitman: Blood Money, which take players to locations across the United States of America. The cut-scenes are narrated by an ex-director of the FBI who has been tracking the International Contract Agency for two years and is being interviewed at his home by a journalist. The story starts off at an abandoned amusement park where many people were killed after a Ferris Wheel collapsed, and after the owner Joseph "Swing King" Clarence was cleared of all charges, people were unhappy, and one father contacts the agency to have the Swing King killed. It soon becomes clear that a rival agency, known as The Franchise has been killing the ICAs agents, and Diana Burnwood closes down the Agency, and has Agent 47 take out the hitmen coming after them then splits the funds between herself and 47. After this happens, an old friend of 47 known as Agent Smith contacts 47, who rescues him from a rehab centre and he then gives 47 a new job. He asks him to take out several assassins who intend to take out the President before the election. Had they succeeded, the President would not have been able to put forward his pro-cloning stance and they would have been able to monopolise the technology which created 47. On successfully eliminating his targets, 47 escapes to his hideout to be free from the many people who are hunting him down where he receives an unexpected visit from Diana who proposes a plan for them both to escape their troubles, but then injects 47 with a death serum. At the funeral, 47 is to be cremated to destroy his bone marrow, and there are armed guards around the area. Diana is inducted into the Franchise, and she places 47's Silverballers on his chest, then applies lipstick and kisses him. It turns out that the lipstick was actually a reverse to the serum that was actually a fake death serum. 47 soon wakes up to kill everyone at the funeral, leaving no witnesses, including the priest and the ex-FBI director. At the end a scene is shown with Diana who has re-opened the Agency which overlooks Copenhagen harbour, and says that she has lost track of 47. After this a scene is played which shows 47 in a brothel talking to a Chinese man, who leads him through to the back.

In Hitman: Blood Money, several new features of gameplay became available to players which were not available in previous Hitman games, and along with this, many old features also made a return. As well as the major ones listed below, Agent 47 can now sedate people rather than kill them, he can hide bodies in things such as freezers, he can hide in closets, and he can play around with power fuses to get through heavily guarded areas without being seen.

One of the major new features which did not appear in Hitman: Contracts or any of the earlier games in the series is the ability to make a death look like an accident. For example, he could tamper with a chandelier to make it fall on a target, and the people in the area would not regard this as suspicious and so nobody would suspect 47. This can really help, as every job results in a newspaper article being printed, and if it looks like a murder, people will suspect 47 in later missions, and the missions later on will become harder.

As per usual in the Hitman series, Agent 47 can take the clothes from any male person who is unconscious or deceased, and he can use this to his advantage. For example, if he was to steal a police uniform, he may be granted access to area which he could not usually get to, or he could use his disguise to lose heat. If, however, somebody finds a body whose clothes have been taken and this gets reported, will become aware of this. So, if somebody was to find a policeman with his uniform stolen, then they would be on the lookout for a suspicious looking policeman.

Another new feature in the game is the ability to gain money from a job. The better it is carried out, the more money you receive, which can be used to buy upgrades for weapons which can be used to your advantage in some missions, especially to get a sniper rifle through a metal detector and scanner.

Another major returning feature is ragdoll physics, which means that people are killed in a somewhat realistic manners, so if they were shot at close range with a shotgun, they would be blasted backwards with arms flailing, whilst a shot to the head with a pistol would mean them dropping dead. This also gives 47 the ability to drag bodies to a more secretive location where they are less likely to be found, or if it is available he could stash them in something like a freezer.

Before starting the game, players can choose what difficulty level they wish to play with. The higher the difficulty level, the more challenging the game becomes, with the number of saves permitted dropping and the artificial intelligence levels increasing greatly.

Throughout the course of the game there are several bits of hidden content which players can see by doing certain things. For example in one mission, Amendment XXV, players can get every guard in the White House to line up and start dancing by throwing their briefcase at a certain wall three times. Small things like this occur in different missions, and are known as easter eggs.